Sepsis is clinically characterized as a systemic inflammatory response to infection, but it can also arise from trauma or injury [1-5]. Sepsis is clinically characterized as a systemic inflammatory response to infection, but it can also arise from trauma or injury [1-5]. Sepsis is a serious medical problem and scientific challenge with a significant unmet need, as it is the leading cause of death among patients in Intensive Care Units (ICU) worldwide. Mortality rates range from 20% for sepsis, to 40% for severe sepsis, and >60% for septic shock [2-4]. Current therapies target the symptoms of sepsis and are geared to support cardiovascular and respiratory function, but they do not specifically address the underlying causes of the inflammatory disease, which involves a dysregulated or poorly balanced innate inflammatory response [1, 4, 10, 12]. The overall lack of improvement in sepsis survival rates, despite significant advances in supportive intensive care, indicates an unmet need in effective target-directed anti-sepsis therapies.
Sepsis is caused by the loss of homeostatic balance during the innate immune response to infection or injury [1, 2]. The innate immune response is driven primarily by signaling molecules collectively referred to as cytokines, which are used by cells of the immune system to communicate the integrity of the body's barriers to the environment. Cytokines are normally produced by immune cells in response to pathogen-associated molecules (PAMPs) or damage-associated molecules (DAMPs), and activate other immune cells to increase the body's immune response. There are two main classes of clinically relevant cytokines: pro-inflammatory mediators that activate and amplify inflammation and anti-inflammatory mediators that impede and balance the inflammatory response. A predominant belief amongst immunologists is that an unrestrained pro-inflammatory mediator cascade causes disease [1, 2, 4-12]. The dysregulated sequence of pro-inflammatory cytokines leading to disease has been referred to as a “cytokine storm” [13] or “inflammatory cascade” [14], as one cytokine typically leads to the production of multiple other cytokines to reinforce and amplify the immune response.
Pro-inflammatory mediators can be further broken down into two subgroups: early mediators and late mediators [1, 2, 19, 20]. Early mediators (tumor-necrosis factor, interleukin-1, interleukin-6, etc.) are not sufficient therapeutic targets for re-establishing homeostatic balance because they are resolved within the time frame of a patient's travel to a clinic to receive medical attention [1,10-12, 18, 19]. Conversely, late mediators can be therapeutically targeted as they fall later in the “inflammatory cascade,” after a patient has realized that he or she has fallen ill. A promising example of targeting a late mediator for therapeutic benefit comes with high mobility group box 1 (HMGB1) [2,10-12, 15-20].
HMGB1 is a powerful late-acting cytokine that plays an important role in the pathogenesis of many inflammatory diseases. Blockade of the cytokine activity of HMGB1 through a variety of different methods improves the outcome in animal models of sepsis, rheumatoid arthritis, and other inflammatory diseases [15, 16]. However, HMGB1 also has key roles in promoting wound healing and the resolution of inflammation, which potentially confounds its value as a therapeutic target [15, 17]. Therefore, there has been a need to seek out other late-acting inflammatory cytokines with potentially fewer pleiotropic effects as therapeutic targets in inflammatory disease.